Examining thyroid hormone synthesis feedback loops as xenobiotic target for brominated flame retardant metabolites

检查甲状腺激素合成反馈回路作为溴化阻燃剂代谢物的异生素靶标

• 批准号: 10193280
• 负责人: Joseph H Bisesi
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193280
• 关键词: Address; Affinity; Anabolism; Attention; Biological Assay; Blood; Body Fluids; Cell Line; Cells; Chemicals; Conflict (Psychology); Consumption; Data; Environment; Epidemiology; Epigenetic Process; Exposure to; Feedback; Flame Retardants; Functional disorder; Future; Hormones; House Dust; Hypothalamic structure; Hypothyroidism; Impairment; Knowledge; Light; Link; Literature; Measurable; Measures; Messenger RNA; Metabolic; Metabolite Interaction; MicroRNAs; Natural Products; Nature; Neurodevelopmental Deficit; Neurons; Pathway interactions; Pattern; Phase; Pituitary Gland; Plasmids; Play; Process; Production; Protein Isoforms; Receptors, Adrenergic, beta-1; Regulation; Reporter; Reporting; Research; Research Proposals; Role; Seafood; Source; Structure; System; Testing; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormone Receptor beta 2; Thyroid Hormones; Thyrotropin-Releasing Hormone; Toxic effect; Xenobiotics; desensitization; design; environmental chemical exposure; epidemiology study; experimental study; exposed human population; exposure route; hormone biosynthesis; in silico; in vivo; insight; marine organism; novel; polybrominated diphenyl ether; receptor; receptor expression; receptor function; reproductive; response

Project Summary Polybrominated diphenyl ethers (BDEs) were used as flame retardants until they were phased out in the USA several years ago due to concerns about their environmental persistence and toxicity. However, continued human exposure to BDEs is well established and is linked to neurodevelopmental deficits and disruption of circulating thyroid hormones. While most studies have focused on interactions of these contaminants with thyroids receptors involved in reproductive and metabolic functions, little attention has been paid to mechanisms involving thyroid hormone biosynthesis pathways. In light of the epidemiological associations between BDE exposure and circulating thyroid hormone levels, and the lack of studies that examine the mechanistic drivers of this phenomenon, the overall scientific premise of this proposal is that exposure to OH-BDEs disrupts the negative feedback inhibition of thyroid hormone biosynthesis. Modulation of this important biosynthesis pathway may be the missing link to explain the epidemiological associations between BDEs in the blood and hypothyroidism. We posit that there are two understudied mechanisms through which BDEs and their metabolites may modulate circulating thyroid hormones. The first mechanism will examine OH-BDE metabolites interactions with the thyroid hormone receptor beta 2 (TRβ2), a thyroid receptor isoform found exclusively in the hypothalamus and pituitary where it is involved in feedback inhibition of thyroid hormone synthesis. The second mechanism will examine indirect modulation of thyroid receptor function by OH-BDE-via epigenetic mechanisms, specifically miRNAs. We propose two highly independent but related specific aims to address these knowledge gaps. These studies are designed to test hypotheses related to OH-BDE regulation of upstream hypothalamic feedback loops that control circulating levels of thyroid hormone. Specific aim 1 will test the hypothesis that OH- BDEs will antagonize the hypothalamic and pituitary specific thyroid receptor, TRβ2, ultimately decreasing thyrotropin-releasing hormone (TRH) in hypothalamic neuronal cells. These hypotheses will be tested using thyroid hormone receptor reporter assays and a hypothalamus cell line. Specific aim 2 will test the hypothesis that thyroid hormone receptor expression is repressed in the hypothalamus by miRNA regulators in the presence of OH-BDEs. This hypothesis will be tested by measuring miRNA regulators of TRs in hypothalamic cells in relation to TRs expression and TRH. If hypothalamic miRNA regulators of TRs correlate to changes in synthesized TRH, we will conclude that miRNAs are key regulators by which OH-BDEs impose negative effects on the thyroid system. Completion of these aims will lend mechanistic insight into the observed thyroid effects associated with exposure to brominated flame retardants. These assays are adaptable to other thyroid hormone disruptors and this mechanism may be significant in regulating circulating levels of thyroid hormones following environmental chemical exposures. Results from these studies will lend important evidence to support future in vivo research proposals focused on these mechanisms.

项目概要 多溴二苯醚 (BDE) 曾被用作阻燃剂，直到在美国被逐步淘汰 几年前，由于担心其环境持久性和毒性，但仍在继续。 人类接触 BDE 已得到充分证实，并且与神经发育缺陷和神经功能紊乱有关。 虽然大多数研究都集中在这些污染物与循环甲状腺激素的相互作用上。 甲状腺受体参与生殖和代谢功能，但其机制却很少受到关注 鉴于 BDE 之间的流行病学关联。 暴露和循环甲状腺激素水平，以及缺乏检查其机制驱动因素的研究 对于这种现象，该提案的总体科学前提是接触 OH-BDE 会扰乱 甲状腺激素生物合成的负反馈抑制。这一​​重要生物合成的调节。 途径可能是解释血液中 BDE 与 BDE 之间流行病学关联的缺失环节。 我们假设 BDE 及其相关机制有两种尚未得到研究的机制。 代谢物可能会调节循环甲状腺激素。第一个机制将检查 OH-BDE 代谢物。 与甲状腺激素受体β2（TRβ2）的相互作用，甲状腺激素受体β2是一种仅在体内发现的甲状腺受体亚型 下丘脑和垂体参与甲状腺激素合成的反馈抑制。 该机制将检查 OH-BDE 通过表观遗传机制对甲状腺受体功能的间接调节， 特别是 miRNA，我们提出了两个高度独立但相关的具体目标来解决这些知识。 这些研究旨在检验与 OH-BDE 上游下丘脑调节相关的假设。 控制甲状腺激素循环水平的反馈回路 具体目标 1 将检验 OH- 的假设。 BDE 会拮抗下丘脑和垂体特异性甲状腺受体 TRβ2，最终降低 下丘脑神经元细胞中的促甲状腺激素释放激素（TRH）将使用以下方法进行检验。 甲状腺激素受体报告基因检测和下丘脑细胞系将检验这一假设。 下丘脑中甲状腺激素受体的表达受到 miRNA 调节因子的抑制 该假设将通过测量下丘脑细胞中 TR 的 miRNA 调节因子来检验。 TRs 表达和 TRH 的关系是否与 TRs 的下丘脑 miRNA 调节因子相关。 合成的 TRH，我们将得出结论，miRNA 是 OH-BDE 施加负面影响的关键调节因子 完成这些目标将有助于深入了解观察到的甲状腺效应。 与接触溴化阻燃剂相关的这些适用于其他甲状腺测定激素。 干扰物，这种机制可能对调节甲状腺激素的循环水平具有重要意义 这些研究的结果将为支持未来的研究提供重要证据。 体内研究提案集中在这些机制上。